P622: GENETIC MARKERS AND OUTCOME OF CLL PATIENTS IN COMBINED TIME-LIMITED TREATMENT WITH ANTI-CD20 ANTIBODY + IBRUTINIB, IDELALISIB OR VENETOCLAX IN THE GCLLSG CLL2-BAG, -BCG, -BIG AND -BIO PHASE-II TRIALS
Authors: Deyan Yosifov, Julia von Tresckow, Adam Giza, Sandra Robrecht, Christof Schneider, Billy Jebaraj, Daniel Mertens, Matthias Ritgen, Anke Schilhabel, Karl-Anton Kreuzer, Anna Maria Fink, Othman Al-Sawaf, Petra Langerbeins, Kirsten Fischer, Barbara Eichhorst, Michael Hallek, Hartmut Döhner, Stephan Stilgenbauer, Paula Cramer, Eugen Tausch
Journal: HemaSphere (2023)

Background: Genetic markers are strong prognostic factors in chronic lymphocytic leukemia (CLL) in the context of chemoimmunotherapy, but their prognostic impact is less clear with combination treatments based on drugs targeting BTK or BCL2. Four phase-2 trials of the German CLL Study Group evaluated time-limited combination regimens in treatment-naïve or relapsed/refractory CLL: BAG (venetoclax-obinutuzumab), BCG (idelalisib-obinutuzumab), BIG (ibrutinib-obinutuzumab) and BIO (ibrutinib-ofatumumab), with or without initial debulking with bendamustine. Aims: To establish the impact of genetic markers on outcome, as well as on clonal stability from baseline to relapse, for the full set and for separate trials. Methods: Of the full set of 242 patients, 224 (93%) received at least 2 treatment cycles and had provided pretreatment tumor material for FISH (n=221), IGHV sequencing (n=221), karyotyping (n=182) and targeted NGS (n=223). Samples were available from 42 of 74 documented relapsed patients (in total 44 relapsed cases as 2 patients participated in 2 trials). To quantify clonal stability, we devised and used a metric called change score (CS). The CS is high (>20) when at least one gene variant or chromosome aberration undergoes a considerable shift in frequency (>0.2) relative to the median shift of the remaining ones. Results: Of the 224 patients, 50% were pretreated (median of 2 prior therapies), 71% had unmutated IGHV (U-IGHV) and 38.5% a complex karyotype (CKT, ≥3 aberrations). Based on the hierarchical model, 17.6% were classified as del(17p), 21.3% as del(11q), 12.7% as tri(12), 21.3% as normal karyotype and 27.1% as del(13q). Mutations were found in TP53 (28.3%), SF3B1 (21.1%), NOTCH1 (16.6%), ATM (14.8%), XPO1 (9.4%), NFKBIE (9.4%), RPS15 (9.1%), BIRC3 (6.3%), EGR2 (5.8%), POT1 (5.8%), BRAF (4.4%), FBXW7 (3.1%) and MYD88 (0.9%). At the end of induction, the overall response rate (ORR) was lower for cases with U-IGHV (93% vs. 100% in M-IGHV, p=0.03) and TP53mut (88.9 vs. 96.9 %, p=0.017). The uMRD rate was lower with TP53mut (33.3% vs. 53.8%, p=0.006) and ranged from 25.6% in patients with del(17p) to 71.4% in tri(12) cases (p=0.006). After a median follow up of 38.6 months, there were 88 events for progression-free survival (PFS) and 30 for overall survival (OS). U-IGHV (HR 3.0, p<0.001), CKT (HR 2.0, p=0.004), del(17p) (HR 2.0, p=0.006), TP53mut (HR 2.3, p<0.001) and NOTCH1mut (HR 1.8, p=0.02) were adverse prognostic factors for PFS. Similar results were obtained in separate analyses for BAG and BIO/BIG/BCG with HR 3.0, p=0.071 and HR 3.2, p=0.002, for U-IGHV and TP53mut, respectively, in the BAG trial, and HR 3.1, p=0.003 and HR 1.9, p=0.013, respectively, in BIO/BIG/BCG. Adverse prognostic markers for OS were CKT (HR 3.4, p=0.003), del(17p) (HR 3.6, p<0.001), del(13q) (HR 2.5, p=0.025) and TP53mut (HR 4.3, p<0.001). Multivariable analysis for PFS identified only prior treatment (HR 3.3, p<0.001), U-IGHV (HR 2.7, p=0.006) and CKT (HR 1.9, p=0.008) as independent prognostic factors. More clonal changes (CS>20) were observed in BAG (13/16) than in BIO/BIG/BCG (14/26), while 2 cases (BAG) were excluded due to no traceable abnormalities. At a median treatment duration of 11 cycles in BIO/BIG/BCG and 8 cycles in BAG, 2 patients acquired BTK C481S mutations at relapse, while no BCL2 mutations were detected. Summary/Conclusion: Genetic risk factors such as the IGHV mutation status remain significant prognostic factors for PFS in the context of time-limited treatment with targeted drugs. Acquisition of high-risk markers was rare and resistance mutations were only acquired in 2 of 44 cases.Keywords: Chronic lymphocytic leukemia, ibrutinib, Prognostic factor, Venetoclax